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Research Focus

Molecular Mechanisms of Cancer Metastasis

The difference between life and death for most cancer patients hinges on the degree of spread, or metastasis, of their tumors. Therefore, a better molecular understanding of cancer metastasis holds significant promise for reducing mortality and morbidity from cancer. The central theme of our research is a multidisciplinary and integrative approach to the analysis of the molecular basis of cancer metastasis, combining molecular biology and genomics tools with animal models and advanced in vivo imaging technologies. We focus on the identification of metastasis genes and functional characterization of their involvement in tumor-stromal interactions during the formation of metastasis in different organs. We are also interested in regulators of mammary gland development and early oncogenic events that may have significant impact on tumor progression and metastasis.

Identification of novel metastasis genes through integrative genomics

Discovering metastasis genes that are clinically relevant and functionally important are critical for the development of novel therapeutics. We use two complementary approaches to harness the power of comprehensive profiling technologies, including genomics, proteomics and metabolomics, for the identification and validation of novel metastasis genes and pathways. Using a large collection of mouse models of cancer metastasis available in our laboratory, we identify candidate metastasis genes by genomic profiling of highly metastatic cells derived after in vivo selection. Functional characterization of these genes revealed the novel activities of several developmentally conserved pathways, including the EGFR, TGFb, and Notch pathways, in mediating tumor-stromal interactions essential for the formation of metastasis in vital organs such as bone, lung and brain. Importantly, pharmaceutical inhibitors against these signaling pathways are highly effective in reducing the development of metastasis, suggesting novel avenues for clinical management of metastatic cancer. We also developed integrative genomics strategies to utilize available clinical genomic profiling and sequencing data of human cancer to identify genetic alterations with functional impact on cancer metastasis. Using this approach, we identified Metadherin (MTDH) as a dual-functional gene that promotes metastasis and broad-spectrum chemoresistance of breast cancers. Ongoing studies in the lab are currently characterizing MTDH and additional candidate metastasis genes.

It has become well-recognized that metastatic cancer cells do not act autonomously when they escape from the primary tumor and establish colonies at different organs. Rather, intricate interactions between tumor cells and their stromal microenvironment play an essential role in the pathogenesis of metastasis. Our laboratory uses a series of in vitro and in vivo models systems to dissect the molecular cross-talks between tumor cells and resident stromal cells. Advanced in vivo imaging technologies are being developed in the lab to analyze the signaling pathway dynamics and cellular interactions that occur at real time during the development and treatment of metastatic diseases. Such studies are crucial for the development of highly effective therapeutics against metastatic cancer.

The role of mammary gland stem cells in development and breast cancer

Although it was initially believed that metastasis capacity is acquired late during tumor progression, substantial evidence suggests that different early transformation events may set the resulting tumors on distinct paths towards either aggressive metastasis or slow progression. In recent years, the intriguing link between mammary stem cells (MaSCs) and breast cancer stem cells has generated tremendous interest due to its important implications in breast cancer etiology and therapeutics. Identifying the cellular origin of breast cancer will not only aid in understanding the early events that drive breast carcinogenesis, but will also yield critical insights to help understand the different tendencies of metastasis in different subtypes of breast cancer. In order to facilitate the study of MaSCs during tumorigenesis and metastasis, we recently developed a mouse model in which MaSCs can be detected by MaSC-specific expression of luciferase in the mammary epithelium. Using this model system, we will now investigating the regulation of MaSCs by canonical stem cell signaling pathways and breast cancer oncogenes, test the susceptibility of MaSCs, progenitor cells and differentiated cells to transformation, and study how the tumorigenic and/or metastatic potential of the resulting tumors are influenced by their cellular origin.

miRNAs and ncRNAs as regulators of tumor progression

miRNAs and other non-coding RNAs (ncRNAs) have emerge in recent years as important regulators of critical physiological and pathological processes. We recently discovered the miR-200 family of miRNAs as important regulators of epithelial-mesenchymal transition, which is believed to be the initial step of metastasis that enables the migration and invasion of tumor cells. We are using xenograft and transgenic mouse models to investigate the function of EMT-related miRNAs. Similar research strategy is being applied to identify and characterize other miRNAs and ncRNAs that may play a crucial role in different stage of tumor progression.